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ANAT242 > Lecture 22- Post Synaptic Mechanism/ modulation > Flashcards

Lecture 22- Post Synaptic Mechanism/ modulation Flashcards

1
Q

Is long term potention are pre-synaptic or post-synaptic mechanism?

A

Post-synaptic

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2
Q

What opposes LTP?

A

-LTD (Synaptic transmission weakening)

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3
Q

How does LTD occur?

A
  • Repetitive low frequency stimulation results in a low level Ca2+influx through NMDARs
  • Low levels of Ca2+ activate protein phosphatases
  • Remove phosphates from AMPA receptor and other targets
  • Removes AMPA receptors from membrane
  • Also, long term changes to gene expression
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4
Q

What exists to balance the processes of LTP and LTD?

A

Modulation: Preserves a relative enhancement of synaptic transmission

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5
Q

What is the debate regarding the Mechanisms underpinning long-lasting synaptic change?

A

-Whether it occurs presynaptically (Neurotransmitter release)

-or postsynaptically (Receptor trafficking, local protein synthesis, gene expression, receptors)

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6
Q

For the AMPA-subtype of glutamate receptors what are AMPAR subunits? How do they assemble?

A
  • GluA1–GluA4
  • Assemble as dimers-of-dimers to form
  • hetero-tetrameric receptors
    or
  • homomeric receptors (GluA1)
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7
Q

What is the effect of glutamate binding to AMPA- receptors?

A

Glutamate binding opens the channel
- Influx of Na+ ions
- Efflux of K+
- Depolarization

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8
Q

How are the AMPA-subtype of glutamate receptors regulated?

A

GluA2 subunits undergo RNA editing
* Glutamine - arginine (Q/R editing)
* Prevents Ca2+-influx

GluA2-containing AMPARs are largely Ca2+- impermeable
* GluA2-lacking AMPARs are Ca2+ permeable

Phosphorylation of GluA1 by CaMKII
* Serine831 enhances single channel conductance

Phosphorylation GluA1 by PKA
* Serine845 enhances open probability and important for
retention at the plasma membrane

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9
Q

What is the lasting effect of strong NMDAR activation?

A

An increase in number of AMPARs at activated synapses

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10
Q

What is meant by the phrase that AMPARs are highly dynamic? What does this mean?

A

AMPARs shuttle into (or out of) synapses
* Results in long-lasting changes in synaptic strength

Lateral mobility
*Along the cell surface
* Between synaptic and extra-synaptic regions

Means=
* Increased trafficking to the PSD
* Increased retention in the PSD

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11
Q

What are AMPARs a part of?

A

-Complex protein networks
-So have increased
association with regulatory
molecules when modulated by LTP

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12
Q

How are AMPARs synthesized?

A

Local protein synthesis:
* Polyribosomes are found in spines
* Polyribosomes translocate from dendritic
shafts to spines in response to activity
* mRNA is found in dendrites
* mRNA is translated in response to activity

Glutamate receptors are synthesised locally
from pre-existing mRNA

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13
Q

What is CREB and what is it’s function?

A

cAMP response element binding protein
- initiates new gene expression

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14
Q

What are intermediate early genes? What do they do?

A

-Transcription factors: Egr1, AP1(fos/jun)
-Amplification of gene expression

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15
Q

What are Secondary response genes? What do they do?

A

Receptors and many others
-New synapses
-Larger synapses
-Re-structured synapses?

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16
Q

What do lasting memories require?

A

-New gene expression

17
Q

What changes occur immediately and then after time in terms of memories?

A

-Within hours-days= plasticity transcriptome i.e. synaptic restructuring, and an epigenetic blockage

-Within days- weeks= maintenance transcriptome

18
Q

How does Alzheimer’s begin?

A

Begins with synaptic dysfunction

19
Q

What is the amyloid Cascade Hypothesis for alzheimer’s?

A

-Amyloid-ß aggregation and plaque formation is the central event
-Leads to neuronal degeneration and
clinical symptoms

20
Q

What ways does receptor dysfunction effect Alzheimer’s disease?

A
  • Aβ causes an initial hyperexcitability of
    neurons
  • due to spillover and excessive levels of glutamate in
    the extrasynaptic space, leading to overstimulation
    of NMDA receptors and subsequently synaptic loss
    and cell death.
  • Aβ-induced endocytosis of the AMPA-type
    glutamate receptors
  • leads to long-term depression
  • Aβ disrupts actin dynamics
  • leading to impairments in the trafficking of AMPA,
    NMDA
  • Aβ interacts with adhesion molecules
  • affects their expression and synaptic localization,
  • impaired integrity of synapses
  • leading to the disruption of neuronal networks in AD
21
Q

What ways does receptor dysfunction effect Alzheimer’s disease?

A
  • Aβ causes an initial hyperexcitability of
    neurons
  • due to spillover and excessive levels of glutamate in
    the extrasynaptic space, leading to overstimulation
    of NMDA receptors and subsequently synaptic loss
    and cell death.
  • Aβ-induced endocytosis of the AMPA-type
    glutamate receptors
  • leads to long-term depression
  • Aβ disrupts actin dynamics
  • leading to impairments in the trafficking of AMPA,
    NMDA
  • Aβ interacts with adhesion molecules
  • affects their expression and synaptic localization,
  • impaired integrity of synapses
  • leading to the disruption of neuronal networks in AD
22
Q

How might glutamate receptors be therapeutic targets for Alzheimer’s disease?

A

Memantine: antagonist of the NMDA receptor subtype of glutamate receptor. It is used to slow neurotoxicity.

  • Researchers at Genentech recently developed a small molecule (GNE-0723) that selectively enhances GluN2A function, thus
    boosting synaptic NMDAR signalling.
  • The researchers tested this in mouse models of Alzheimer’s
    and epilepsy.
  • In both conditions, inhibitory interneurons flounder, leading to
    too much synchronized neuronal activity.
  • Treatment reduced abnormal low-frequency oscillations and
    epileptiform bursts
  • Improved Morris water maze performance
23
Q

What does sAPPa do?

A

-enhances plasticity
-enhances protein synthesis
-enhances GluA1 synthesis

24
Q

What is FUNCAT-PLA?

A

Fluorescence non-canonical amino acid tagging- proximity ligation assay:

-non-canonical amino acid taken up into cells and are labelled with proteins (only newly made ones are labelled).

-The proteins used are a nuclei acids. Have two so can hybridize creating a platform for fluorescent tag

-They are then localised using “click chemistry” & the
proximity ligation assay

ANAT242 (25 decks)

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